IL-6 is a cytokine also called B-cell stimulating factor 2 (BSF2) or interferon β2. IL-6 was discovered as a differentiation factor involved in the activation of B-cell lymphocytes (Non-Patent Document 1), and was later revealed to be a multifunctional cytokine that influences the function of various cells (Non-Patent Document 2). IL-6 has been reported to induce maturation of T lymphocyte cells (Non-Patent Document 3).
IL-6 transmits its biological activity via two kinds of proteins on cells. The first is the IL-6 receptor, which is a ligand binding protein to which IL-6 binds, with a molecular weight of about 80 kDa (Non-Patent Documents 4 and 5). The IL-6 receptor is present in a membrane-bound form that penetrates and is expressed on the cell membrane, and also as a soluble IL-6 receptor that mainly consists of the extracellular region of the membrane-bound form.
The other kind of protein is the membrane protein gp130, which has a molecular weight of about 130 kDa and is involved in non-ligand binding signal transduction. The biological activity of IL-6 is transmitted into the cell through formation of an IL-6/IL-6 receptor complex by IL-6 and IL-6 receptor, followed by binding of the complex with gp130 (Non-Patent Document 6).
IL-6 inhibitors are substances that inhibit the transmission of IL-6 biological activity. Currently, known IL-6 inhibitors include antibodies against IL-6 (anti-IL-6 antibodies), antibodies against IL-6 receptor (anti-IL-6 receptor antibodies), antibodies against gp130 (anti-gp130 antibodies), IL-6 variants, partial peptides of IL-6 or IL-6 receptor, and such.
There are several reports regarding anti-IL-6 receptor antibodies (Non-Patent Documents 7 and 8, and Patent Documents 1 to 3). One such report details a humanized PM-1 antibody, which is obtained by transplanting the complementarity determining region (CDR) of mouse antibody PM-1 (Non-Patent Document 9), which is an anti-IL-6 receptor antibody, into a human antibody (Patent Document 4).
Due to advances in multidrug therapy and clinical application of various immunosuppressants, therapeutic strategies for the acute rejection reaction that follow organ transplantation are almost established, and the one-year survival rate after various organ transplantations has been significantly improved. However, the chronic rejection reaction, which becomes problematic from after a year following transplantation, occurs even in clinical cases where the acute rejection reaction has been overcome by conventional immunosuppressive therapy, and where that therapy has been continued for a long term. Thus, neither preventive nor therapeutic methods effective against the chronic rejection reaction have been established. Furthermore, the mechanism behind this pathological condition has not been fully elucidated, and it is difficult to diagnose it compared to the acute rejection reaction. Thus, the chronic rejection reaction is known to be a complication that affects long-term prognosis in recipients (Non-Patent Documents 10 and 11).
Known pathological features characteristic of the chronic rejection reaction include fibrosis of interstitium and stenosis of lumens due to intimal thickening of luminal tissues in transplanted organs. In particular, angiostenosis is an important pathological feature, and is referred to as post-transplantation vascular lesion or post-transplantation arteriosclerosis. A variety of factors is thought to intricately influence the progression of the pathological condition, such as prolongation of the rejection reaction by both cellular and humoral immunity, ischemia-reperfusion disorders of organs, functional disorders of vascular endothelia, common risk factors for arteriosclerosis (diabetes, hyperlipidemia, hypertension, and the like) in recipients, side effects of immunosuppressants, genetic factors, and post-transplantation infection of cytomegalovirus (Non-Patent Documents 12 and 13).
Among existing pharmaceutical agents, calcineurin inhibitors such as cyclosporine and tacrolimus in particular are ineffective towards the chronic rejection reaction, and their side effects such as hypertension, hyperlipidemia, and diabetes are considered problematic. Further, long-term immunosuppressive therapy after transplantation is required in pediatric recipients in particular. Thus, the development of pharmaceutical agents effective for the chronic rejection reaction and having few side effects (Non-Patent Documents 13 and 14) has been anticipated.
The above-described requirement to develop a novel immunosuppressive therapy for suppressing the chronic rejection reaction is the background of the present study.
Documents of related prior arts for the present invention are described below.    [Patent Document 1] International Patent Application Publication No. WO 95/09873    [Patent Document 2] French Patent Application No. FR 2694767    [Patent Document 3] U.S. Pat. No. 5,216,128    [Patent Document 4] WO 92/19759    [Non-Patent Document 1] Hirano, T. et al., Nature (1986) 324, 73-76    [Non-Patent Document 2] Akira, S. et al., Adv. in Immunology (1993) 54, 1-78    [Non-Patent Document 3] Lotz, M. et al., J. Exp. Med. (1988) 167, 1253-1258    [Non-Patent Document 4] Taga, T. et al., J. Exp. Med. (1987) 166, 967-981    [Non-Patent Document 5] Yamasaki, K. et al., Science (1988) 241, 825-828    [Non-Patent Document 6] Taga, T. et al., Cell (1989) 58, 573-581    [Non-Patent Document 7] Novick, D. et al., Hybridoma (1991) 10, 137-146    [Non-Patent Document 8] Huang, Y. W. et al., Hybridoma (1993) 12, 621-630    [Non-Patent Document 9] Hirata, Y. et al., J. Immunol. (1989) 143, 2900-2906    [Non-Patent Document 10] Wong, B. W. et al., Cardiovasc. Pathol. (2005) 14, 176-80    [Non-Patent Document 11] Hornick, P. et al., Methods Mol. Biol. (2006) 333, 131-44    [Non-Patent Document 12] Ramzy, D. et al., Can. J. Surg. (2005) 48, 319-327    [Non-Patent Document 13] Valantine, H., J. Heart Lung Transplant (2004) 23(5 Suppl), S187-93    [Non-Patent Document 14] Webber, S. A. et al., Lancet (2006) 368, 53-69    [Non-Patent Document 15] Izawa, A., et al., Circ. J. (2007) 71(Suppl I), 392 (Annual Scientific Meeting of the Japanese Circulation Society, Kobe, Mar. 15-Mar. 17, 2007; Abstract PE-269)    [Non-Patent Document 16] Izawa, A., et al., Am. J. Transplant. (2007) 7(Suppl 11), 426 (American Transplant Congress, San Francisco, Calif., Mar. 5-Mar. 9, 2007; Abstract 1084)